WO2025058412A1 - Prodrug of norepinephrine reuptake inhibitor and preparation method therefor - Google Patents

Abstract

The present invention relates to a novel prodrug of the active metabolite of atomoxetine. The present invention also relates to a pharmaceutically acceptable salt of the atomoxetine prodrug, a pharmaceutical composition containing same, a combination, or a use thereof. The novel prodrug of the active metabolite of atomoxetine has an effect of treating or preventing attention-deficient/hyperactivity disorder (ADHD), cognitive decline, ischemic stroke of a subject.

Description

Prodrug of norepinephrine reuptake inhibitor and method for preparing same

The present invention relates to a prodrug of 4-hydroxy atomoxetine (4-OH ATX), a novel active metabolite of atomoxetine.

The present invention also relates to a pharmaceutically acceptable salt of a prodrug of 4-hydroxy atomoxetine, a pharmaceutical composition, combination or use comprising the same.

The novel 4-hydroxy atomoxetine prodrug has a therapeutic effect on attention-deficit/hyperactivity disorder (ADHD), cognitive decline, or ischemic stroke in subjects.

Atomoxetine is a selective norepinephrine reuptake inhibitor (NSRI) and is a representative drug used to treat attention-deficit hyperactivity disorder (ADHD) in adults and adolescents.

Patent Publication No. 2017-0125271 discloses that atomoxetine can effectively prevent neural damage in the CA1 region of the hippocampus, which is known to be sensitive to cerebral ischemia, based on the fact that it has excellent neuroprotective and neuronal apoptosis inhibition abilities and excellent glial cell activation inhibition abilities, and thus can be usefully used to treat, prevent, and improve ischemic stroke.

Atomoxetine is mainly metabolized in the liver by the CYP2D6 enzyme. CYP2D6 is an enzyme that shows various genetic variations in each person, so the metabolism rate may vary from person to person. In addition, people with active CYP2D6 can metabolize atomoxetine quickly, and in such cases, the blood concentration of atomoxetine remains low. On the other hand, people with inactive or low functioning CYP2D6 can metabolize atomoxetine slowly, and the blood concentration may remain high, which may increase the risk of side effects, and in some cases, the dosage may need to be adjusted.

In addition, when taking atomoxetine with CYP2D6 inhibitors such as bupropion, paroxetine, fluoxetine, and quinidine, the metabolism rate is slowed, which increases the risk of unexpected effects or side effects. Therefore, when prescribing atomoxetine, there is a difficulty in considering the patient's CYP2D6 genotype or the possibility of interaction with CYP2D6 inhibitors.

Accordingly, the present inventors invented a prodrug of a selective norepinephrine reuptake inhibitor with improved storage stability, processability, bioavailability, etc., as a prodrug of 4-hydroxy atomoxetine (4-OH ATX), an active metabolite that is converted by CYP2D6 and exhibits efficacy similar to that of atomoxetine, so that the drug can be used to treat related diseases regardless of CYP metabolism.

The purpose of the present invention is to provide a prodrug of an active metabolite of atomoxetine with improved storage stability, processability, bioavailability, etc. by providing a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof and a method for preparing the same.

To achieve the above objectives:

One aspect of the present invention provides a compound represented by chemical formula 1, 1A, 1B or 1C, or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention provides a method for preparing a compound represented by formula 1 or a pharmaceutically acceptable salt thereof, comprising a step of deprotecting a compound represented by formula 2.

Another aspect of the present invention provides a pharmaceutical composition for preventing or treating attention deficit hyperactivity disorder (ADHD), cognitive dysfunction or ischemic stroke, comprising a compound represented by chemical formula 1, 1A, 1B or 1C or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention provides a method for preventing or treating attention deficit hyperactivity disorder (ADHD), cognitive dysfunction or ischemic stroke, comprising administering to a subject a compound represented by chemical formula 1, 1A, 1B or 1C or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention provides a use of a compound represented by chemical formula 1, 1A, 1B or 1C, or a pharmaceutically acceptable salt thereof, for the prevention or treatment of attention deficit hyperactivity disorder (ADHD), cognitive dysfunction or ischemic stroke.

Another aspect of the present invention provides the use of a compound represented by chemical formula 1, 1A, 1B or 1C, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention or treatment of attention deficit hyperactivity disorder (ADHD), cognitive dysfunction or ischemic stroke.

The compound of the present invention provides a 4-hydroxy atomoxetine prodrug, which is an atomoxetine active metabolite, with improved storage stability, processability, bioavailability, etc., so as to be effective in treating various neurological diseases including attention deficit hyperactivity disorder (ADHD) regardless of CYP metabolism.

However, the effects of the present invention are not limited to the above-mentioned effects, and it should be understood that they include all effects that can be inferred from the composition of the invention described in the detailed description or claims of the present invention.

Figure 1 shows the metabolic pathway of atomoxetine in the body by CYP enzymes.

Figure 2 shows a method for preparing a compound represented by chemical formula 1 by deprotecting a compound represented by chemical formula 2.

Figure 3 shows the in vivo pharmacokinetics of the prodrug of the present invention. P of "-OP" shown in the compound of Figure 3 means a protecting group.

Figure 4 is a graph showing the pharmacokinetic results of atomoxetine, 4-hydroxy atomoxetine, and compounds of Examples 1, 2, and 3 of the present invention.

Figure 5 is a graph showing the results of norepinephrine reuptake inhibition rates of atomoxetine, 4-hydroxy atomoxetine, and compounds of Examples 1, 2, and 3 of the present invention.

1. A compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutical composition, treatment method and use containing the same

One aspect of the present invention provides a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In chemical formula 1,

Z is any one amino acid selected from the group consisting of glycine, phenylglycine, leucine, methionine, valine, alanine, isoleucine, proline, tryptophan, tyrosine, phenylalanine, histidine, serine, cysteine, asparagine, threonine, t-leucine, glutamine, glutamic acid, aspartic acid, lysine, arginine, and 3,4-dihydroxyphenylalanine, or W;

이고; W is

and;

R is H, halogen, C _1-20 alkyl, C _1-20 alkoxy, -OC _1-20 alkyl, -SC _1-20 alkyl, C _1-20 alkenyl, C _1-20 alkynyl, C _3-12 cycloalkyl, heterocycloalkyl having 3 to 12 ring atoms, C _5-10 aryl, heteroaryl having 5 to 10 ring atoms, hydroxy (OH), thiol, amine, ester, carboxyl (COOH), or cyano (CN);

At this time, the amino acid, alkyl, alkenyl, alkynyl and amine may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of C _1-20 alkyl, C _1-20 alkyl substituted with one or more halogens, -OC _1-20 alkyl, -SC _1-20 alkyl, ester, C _1-20 alkyl substituted with cyano, amine substituted with C _1-20 alkyl, carboxyl (COOH), halogen, cyano (CN) and C _1-20 alkylcarbonyl;

The above n is an integer from 0 to 20.

In another aspect of the present invention, Z is an amino acid substituted with C _1-10 alkylcarbonyl; or Z is W, R is an amine substituted with C _1-10 alkyl, C _3-7 cycloalkyl, or C _1-10 alkyl, and n is 0.

In the present invention, the alkylcarbonyl group includes an acetyl group. For example, the amino acid may be substituted with an alkylcarbonyl group, and may be alanine, valine or leucine substituted with an acetyl group.

Another aspect of the present invention provides a compound represented by chemical formula 1A or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1A]

In chemical formula 1A,

The above amino acid is any one amino acid selected from the group consisting of substituted or unsubstituted glycine, phenylglycine, leucine, methionine, valine, alanine, isoleucine, proline, tryptophan, tyrosine, phenylalanine, histidine, serine, cysteine, asparagine, threonine, t-leucine, glutamine, glutamic acid, aspartic acid, lysine, arginine, and 3,4-dihydroxyphenylalanine.

Another aspect of the present invention provides a compound represented by chemical formula 1B or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1B]

In chemical formula 1B,

wherein R is H, halogen, C _1-20 alkyl, C _1-20 alkyl substituted with one or more halogens, -OC _1-20 alkyl, -SC _1-20 alkyl, C _1-20 alkyl substituted with cyano (CN), hydroxy (OH), thiol, amine unsubstituted or substituted with C _1-20 alkyl, ester, carboxyl (COOH), cyano (CN), a substituted or unsubstituted C _3-12 cycloalkyl, a substituted or unsubstituted heterocycloalkyl having 3 to 12 ring atoms, a substituted or unsubstituted C _5-10 aryl, or a substituted or unsubstituted heteroaryl having 5 to 10 ring atoms; and wherein n is an integer of 0 to 20.

Another aspect of the present invention provides a compound represented by chemical formula 1C or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1C]

In chemical formula 1C,

,

또는

이고, A is

,

or

And,

R ₂ is hydrogen, C _1-20 alkyl, C _1-20 alkyl substituted with one or more halogens, -OC _1-20 alkyl, -SC _1-20 alkyl, ester, C _1-20 alkyl substituted with cyano, amine substituted with C _1-20 alkyl, carboxyl (COOH), halogen or cyano (CN).

In the present invention, the term "alkyl" means a saturated straight-chain or branched non-cyclic hydrocarbon having 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, or 1 to 4 carbon atoms (where the carbon number is not particularly limited). Representative saturated straight-chain alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl and -n-decyl, and saturated branched alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, isopentyl, 2-methylhexyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-Dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimethylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-deethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and 3,3-diethylhexyl.

When it is described as “ _1-6 ” or “ ₁ to C ₆ ” in this specification, it means that the number of carbon atoms is 1 to 6. For example, C _1-6 alkyl means alkyl having 1 to 6 carbon atoms.

The terms “halogen” and “halo” as used herein mean fluorine, chlorine, bromine or iodine.

The term "cycloalkyl" as used herein means a monocyclic or polycyclic saturated ring having carbon and hydrogen atoms and no carbon-carbon multiple bonds. In the present invention, the cycloalkyl may contain 3 to 20 ring atoms, preferably 3 to 15 ring atoms, more preferably 3 to 12 or 3 to 7 ring atoms.

Examples of cycloalkyl groups include, but are not limited to, C ₃ -C ₂₀ cycloalkyl, C ₃ -C ₁₅ cycloalkyl, C ₃ -C ₁₂ cycloalkyl or C ₃ -C ₇ cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The cycloalkyl group can be optionally substituted. In one embodiment, the cycloalkyl group is a monocyclic or bicyclic ring.

The term "substitution" as used herein may occur one or more times in each case, and is used as a concept including substitution with a side chain.

As used herein, "heterocycle" means a monocyclic or bicyclic ring having 3 to 20 ring atoms, which is saturated or unsaturated, containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or can mean a monocyclic or bicyclic ring having 3 to 15 ring atoms, or can mean a monocyclic or bicyclic ring having 3 to 12 ring atoms. Or, it means a monocyclic, saturated or unsaturated, bicyclic, heterocyclic ring having 5 to 7 ring atoms, or 7 to 10 ring atoms, wherein the nitrogen and sulfur heteroatoms can be optionally oxidized, and the nitrogen heteroatoms can be optionally quaternized, and includes a bicyclic ring in which some of the heterocycles are fused to a benzene ring. The heterocycles can be linked through heteroatoms or carbon atoms. Representative heterocycles include heterocycloalkyl, morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiphenyl, tetrahydrothypyranyl, tetrahydrothiopyrimidinyl.

The term "aryl" as used herein refers to a carbon ring aromatic group containing 5 to 10 ring atoms. Representative examples include, but are not limited to, phenyl, tolyl, xylyl, naphtyl, tetrahydronaphtyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like. The carbon ring aromatic group can be optionally substituted.

As used herein, "heteroaryl" is an aromatic heterocycle having at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, and having 3 to 20 ring atoms including at least one carbon atom, including mono- and bicyclic ring systems, preferably having 3 to 15 ring atoms, more preferably having 5 to 10 ring atoms. Representative heteroaryls include triazolyl, tetrazolyl, oxadiazolyl, pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, These are pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, quinazolinyl, pyrimidyl, oxetanyl, azepinyl, piperazinyl, morpholinyl, dioxanil, thietanyl, and oxazolyl.

In another aspect of the present invention, the compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof may be any one selected from the group below, but is not limited thereto.

Example 1 (R)-3-Methyl-4-(3-(methylamino)-1-phenylpropoxy)phenyl acetate
((R)-3-methyl-4-(3-(methylamino)-1-phenylpropoxy)phenyl acetate)

2 (R)-3-Methyl-4-(3-(methylamino)-1-phenylpropoxy)phenyl propionate
((R)-3-methyl-4-(3-(methylamino)-1-phenylpropoxy)phenyl propionate)

3 (R)-3-Methyl-4-(3-(methylamino)-1-phenylpropoxy)phenyl isobutyrate
((R)-3-methyl-4-(3-(methylamino)-1-phenylpropoxy)phenyl isobutyrate)

4 (R)-3-Methyl-4-(3-(methylamino)-1-phenylpropoxy)phenyl cyclopropanecarboxylate
((R)-3-methyl-4-(3-(methylamino)-1-phenylpropoxy)phenyl cyclopropanecarboxylate)

5 (R)-3-Methyl-4-(3-(methylamino)-1-phenylpropoxy)phenyl dimethylcarbamate
((R)-3-methyl-4-(3-(methylamino)-1-phenylpropoxy)phenyl dimethylcarbamate)

6 3-Methyl-4-((R)-3-(methylamino)-1-phenylpropoxy)phenyl acetyl-L-alaninate
(3-methyl-4-((R)-3-(methylamino)-1-phenylpropoxy)phenyl acetyl-L-alaninate)

7 3-Methyl-4-((R)-3-(methylamino)-1-phenylpropoxy)phenyl acetyl-L-valinate
(3-methyl-4-((R)-3-(methylamino)-1-phenylpropoxy)phenyl acetyl-L-valinate)

8 3-Methyl-4-((R)-3-(methylamino)-1-phenylpropoxy)phenyl acetyl-L-leucinate
(3-methyl-4-((R)-3-(methylamino)-1-phenylpropoxy)phenyl acetyl-L-leucinate)

The term "purified" as used herein means that the isolate, when separated, is at least 90% pure, in one embodiment at least 95% pure, in another embodiment at least 99% pure, and in yet another embodiment at least 99.9% pure.

In the present invention, the compound of the present invention can provide 4-OH ATX (4-hydroxy atomoxetine), which is an active metabolite of atomoxetine, by an enzyme.

In the present specification, chemical formula 2 represents 4-hydroxy atomoxetine in which the nitrogen is protected by a Boc (tert-butoxycarbonyl) group.

In the present invention, the CYP2D6 enzyme is a type of CYP enzyme (Cytochrome P450), which is mainly involved in drug metabolism, has a great influence on the body kinetics of drugs, and plays an important role in indicating the efficacy and toxicity of drugs. The main enzymes involved in drug metabolism include CYP2C9, CYP2C19, CYP2D6, and CYP3A4, and the abundance ratio of each CYP enzyme varies depending on race, etc. Among them, CYP2D6 is a highly polymorphic gene, and more than 80 variant alleles are known so far.

CYP2D6*3, *4, *5, *6, *7, and *14 alleles are expressed as PM (Poor Metabolizer) genotypes with no enzyme activity or inability to produce enzyme. CYP2D6*10 and *17 alleles have reduced enzyme activity and are expressed as IM (Intermediate Metabolizer), *1 and *2 are expressed as EM (Extensive Metabolizer), and CYP2D6*2×N and *4×N are expressed as UM with enhanced metabolism.

About 7 to 10% of Westerners and about 1% of Asians have the PM trait, and among PMs, about 12 to 21% of Westerners have the CYP2D6*4 allele, about 4 to 6% have the CYP2D6*5 allele, and in Asians, the CYP2D6*5 genotype appears at about 6.2%, and the CYP2D6*4 genotype appears at a low rate of less than 1%. In particular, the CYP2D6*10 allele appears at a frequency of about 33 to 50% in Asians, and in African Americans, PM appears at a rate of 1.9%, and about 9 to 35% have the CYP2D6*17 allele. In addition, several overlapping alleles expressed as UM have been reported, and 2D6*2×2 or *4×2 are known as representative UM alleles, which appear at a rate of about 1 to 10% in Westerners and a relatively high rate of about 30% in Africans.

In the case of atomoxetine, there are differences in the pharmacokinetic profile and adverse drug reactions depending on the CYP2D6 genotype, and in the case of the PM trait of CYP2D6 or when taking it together with CYP2D6 inhibitors such as bupropion, paroxetine, fluoxetine, and quinidine, dosage adjustment is required. Atomoxetine, which has these characteristics, is mainly metabolized by CYP2D6 (Figure 1).

In the case of PM trait of CYP2D6, the metabolism of atomoxetine is inhibited, Cmax (Maximum concentration) increases 5-fold, AUC (Area Under the Curve) increases 10-fold, and the drug half-life, which is usually 5 hours, is prolonged up to 24 hours. In the case of EM of CYP2D6, when taken together with a CYP2D6 inhibitor, the steady-state blood concentration was similar to that of CYP2D6 PM, AUC increased 6 to 8-fold, and Css (Steady-State Concentration) and Cmax increased about 3 to 4-fold.

Concomitant treatment with CYP2D6 inhibitors such as bupropion, paroxetine, fluoxetine, and quinidine increases plasma atomoxetine levels by more than 100%. It also increases the levels of N-dimethyl atomoxetine (N-DM-ATX), which has little pharmacological efficacy and is mainly responsible for side effects, and decreases the plasma levels of 4-hydroxy atomoxetine (4-OH ATX), which has a similar level of activity to atomoxetine, to a similar degree.

Another aspect of the present invention provides a pharmaceutical composition for preventing or treating attention deficit hyperactivity disorder (ADHD), cognitive dysfunction or ischemic stroke, comprising the compound of the present invention or a pharmaceutically acceptable salt thereof.

In the present invention, the “cognitive dysfunction” may be any one selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, agnosia, aphasia, apraxia, and mild cognitive impairment.

In the present invention, the pharmaceutical composition can be administered in the form of a suitable pharmaceutical composition through any suitable route, and in an effective dosage for the intended treatment.

An effective dosage is generally about 0.001 to about 100 mg/kg body weight/day, preferably about 0.5 to about 30 mg/kg/day, given as a single or divided dose.

Depending on age, species, and the disease or condition being treated, dosage levels below the lower end of this range may be appropriate. Alternatively, larger dosages may be used without harmful side effects. Larger dosages may be divided into several smaller doses for administration throughout the day. Methods for determining appropriate dosages are well known in the art.

In the present invention, the pharmaceutical composition can be administered orally or topically.

(1) Oral administration

The compounds of the present invention may be administered orally, which includes swallowing. By oral administration, the compounds of the present invention may enter the gastrointestinal tract, or may be absorbed directly into the bloodstream from the mouth, for example, by buccal or sublingual administration.

Compositions suitable for oral administration may be in the form of solids, liquids, gels, or powders, and may have dosage forms such as tablets, lozenges, capsules, granules, or powders.

The composition for oral administration may optionally be enteric coated, and may exhibit delayed or sustained release through the enteric coating. That is, the composition for oral administration according to the present invention may be a formulation having an immediate or modified release pattern.

In a tablet formulation, the amount of the active ingredient drug can be present in an amount of from about 0.05% to about 95% by weight of the total weight of the tablet, or from about 2% to about 50% by weight of the formulation. Additionally, the tablet can contain a disintegrant, comprising from about 0.5% to about 35% by weight of the formulation, or from about 2% to about 25% by weight of the formulation.

Binders for manufacturing tablets may include gelatin, polyethylene glycol, sugar, gum, starch, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, etc., and suitable diluents for manufacturing tablets may include mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, starch, microcrystalline cellulose, etc., but the present invention is not limited to the types of these additives.

(2) Local administration

The compounds of the present invention can be administered topically, either skin or transdermally. Formulations for topical administration include lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, patches, and the like. Pharmaceutically acceptable carriers for topical administration formulations can include water, alcohol, mineral oil, glycerin, polyethylene glycol, and the like. Topical administration can also be performed by electroporation, iontophoresis, phonophoresis, and the like.

Compositions for topical administration may be formulations having an immediate or modified release pattern, wherein the modified release pattern may be a delayed or a sustained release pattern.

Another aspect of the present invention provides a method for preventing or treating attention deficit hyperactivity disorder (ADHD), cognitive dysfunction or ischemic stroke, comprising administering to a subject a compound of the present invention or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention provides a use of the compound of the present invention or a pharmaceutically acceptable salt thereof for the prevention or treatment of attention deficit hyperactivity disorder (ADHD), cognitive dysfunction or ischemic stroke.

Another aspect of the present invention provides a use of the compound of the present invention or a pharmaceutically acceptable salt thereof for preparing a medicament for the prevention or treatment of attention deficit hyperactivity disorder (ADHD), cognitive dysfunction or ischemic stroke.

The contents of the pharmaceutical composition of the present invention can be equally applied to the above preventive or therapeutic methods, uses and uses for manufacturing medicines.

For example, with respect to the above treatment methods, uses and uses for manufacturing the medicament, "cognitive impairment" may be any one selected from the group consisting of Alzheimer's disease, Parkinson's disease, agnosia, aphasia, apraxia and mild cognitive impairment.

2 . Method for producing a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof

One aspect of the present invention provides a method for preparing a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof, the method comprising a step of deprotecting a compound represented by the following chemical formula 2 (tert-butyl(R)-(3-(4-hydroxy-2-methylphenoxy)-3-phenylpropyl)(methyl)carbamate).

[Chemical Formula 1]

[Chemical formula 2]

Deprotection of the Boc protecting group of the nitrogen in the above chemical formula 2 represents a reaction that can be easily performed by a person skilled in the art using known techniques.

The N-Boc 4-OH ATX of the above chemical formula 2 used in the examples for preparing the compound of the present invention was prepared with reference to the reference WO 2011/027359.

In the present invention, when manufactured using the manufacturing method according to the present invention, it has excellent advantages. More specifically, the present invention can provide 4-hydroxy atomoxetine, which is decomposed by esterase, an enzyme in a living body, and exhibits a norepinephrine reuptake inhibitory effect, and has the advantage of being able to be metabolized regardless of the CYP genotype while having a norepinephrine reuptake inhibitory effect.

4-Hydroxyatomoxetine has pharmacological activity similar to that of the parent drug, atomoxetine, but it is a highly viscous liquid, making it difficult to process and stable when used as an active drug.

In contrast, all of the materials of the examples manufactured according to the present invention are solids, and thus have excellent stability and processability. In addition, the compounds of the present invention have improved photostability by introducing a protecting group to the OH group at the terminal phenyl group, which is the main reason for poor photostability, and the drug acts by an enzyme in the body after administration, thereby increasing the bioavailability of the drug, and the drug exhibits pharmacokinetics in a sustained-release form, thereby improving the convenience of administration for patients, and the drug is better distributed to the brain tissue, which is the site of action, thereby exhibiting better pharmacological efficacy.

Another aspect of the present invention provides a method of manufacturing a compound comprising using any one compound selected from the group consisting of:

a

b

c

d

e

f

g

h

Hereinafter, the present invention will be described in more detail through examples and experimental examples. The following examples and experimental examples are described for the purpose of illustrating the present invention, and the scope of the present invention is not limited thereto.

Manufacturing Example 1: Manufacturing of an intermediate for manufacturing a compound of chemical formula 1

A compound represented by chemical formula 2 was prepared as described below, and based on this, a compound represented by chemical formula 1 was prepared as described in the examples below.

Step 1: Synthesis of tert-butyl (R)-(3-(4-acetyl-2-methylphenoxy)-3-phenylpropyl)(methyl)carbamate

Tert-butyl (R)-(3-hydroxy-3-phenylpropyl)(methyl)(20 g, 75.37 mmol, obtainable from EOS) was dissolved in dimethylacetate amide (300 ml, obtainable from Aldrich), 5N sodium hydroxide solution (53.78 ml, 1.2 eq) was added, and the mixture was stirred at 5 to 20°C. 4-Fluoro-3-methyl acetophenone (20.37 g, 1.2 eq, 90.45 mmol, obtainable from Sigma Aldrich) was added, and the mixture was stirred at 25 to 35°C for 12 hours. The pH was adjusted to pH 3 to 5 using acetic acid (obtained from Sigma Aldrich), and ethyl acetate (300 ml*3 times, obtainable from Sigma Aldrich) was added, stirred for more than 1 hour, and extracted. Ammonium hydroxide solution was added to the extract, and extraction was performed by stirring at room temperature for more than 1 hour. The extract was concentrated under reduced pressure to obtain 23.41 g (yield: 78%) of tert-butyl (R)-(3-(4-acetyl-2-methylphenoxy)-3-phenylpropyl)(methyl)carbamate as a pale yellow solid compound.

Step 2: Synthesis of tert-butyl (R)-(3-(4-hydroxy-2-methylphenoxy)-3-phenylpropyl)(methyl)carbamate (Formula 2)

Tert-butyl (R)-(3-(4-acetyl-2-methylphenoxy)-3-phenylpropyl)(methyl)carbamate (20 g, 50.31 mmol) prepared in Step 1 above was added to toluene (200 ml, available from Sigma Aldrich) and stirred at 50 to 55°C for more than 1 hour. After confirming that it was dissolved, triethylamine (6.11 g, 60.37 mmol, available from Sigma Aldrich) was added and the temperature was increased to 60 to 65°C and stirred for more than 2 hours. Thereafter, the temperature was increased to 80 to 85°C and stirred for an additional 10 minutes.

After concentration of the reaction solution under reduced pressure, a residue was obtained. Methanol (100 ml, obtainable from Sigma Aldrich) was added to the residue, and the mixture was stirred at 40 to 60°C for more than 10 minutes, then ammonium hydroxide solution (obtained from Sigma Aldrich) was added, and the mixture was stirred at 40 to 60°C for more than 17 hours. An aqueous hydrochloric acid solution was added to the reaction solution to adjust the pH to 2 to 2.4, and ethyl acetate (200 ml x 3, obtainable from Sigma Aldrich) was added, stirred for more than 1 hour, and extracted. An ammonium hydroxide solution was added to the extract, adjusted to pH 10 to 11, and extracted by stirring at room temperature for more than 1 hour. An aqueous hydrochloric acid solution was added to the extract, adjusted to pH 1 to 1.2, and extracted by stirring at room temperature for more than 1 hour. The extract was concentrated under reduced pressure to obtain 14.98 g (yield: 80.6%) of a pale yellow solid compound.

1H NMR δ: 8.91(s, 1H), 7.32-7.25(m, 5H), 7.01(d, 1H), 6.74-6.70(m, 2H), 4.88(t, 1H), 3.26(s, 3H), 2.53(t, 2H), 2.24(q, 2H), 2.12(s, 3H)

Example: Preparation of a compound of chemical formula 1

From the compound of chemical formula 2 manufactured in Manufacturing Example 1, a compound represented by chemical formula 1 was manufactured according to Examples 1 to 8 below.

Example 1: Synthesis of (R)-3-methyl-4-(3-(methylamino)-1-phenylpropoxy)phenyl acetate

Dichloromethane (4.25 ml) and triethylamine (0.23 g, 2.31 mmol) were added to tert-butyl (R)-(3-(4-hydroxy-2-methylphenoxy)-3-phenylpropyl)(methyl)carbamate (0.85 g, 2.29 mmol), and the mixture was stirred at room temperature. Then, acetyl chloride (0.22 g, 2.75 mmol) was added, and the mixture was stirred at room temperature for more than 1 hour. Water (2.55 ml) was added to the reaction solution to terminate the reaction, and the organic layer was extracted.

The organic layer was concentrated under reduced pressure. Dichloromethane (6.0 ml) and trifluoroacetic acid (0.78 g, 6.86 mmol) were added to the residue obtained, and the mixture was stirred at room temperature for 2 hours. Water (6.0 ml) was added to the reaction solution, and extraction was performed. The residue obtained by concentrating the extract under reduced pressure was separated by column chromatography (Samjeon Pure Chemical Industries, Ltd.) (15% MC:MeOH) to obtain 0.58 g (yield: 80%) of a white solid compound.

1H NMR δ: 7.32-7.25(m, 5H), 7.11(d, 1H), 7.04(s, 1H), 6.91(d, 1H), 4.88(t, 1H), 3.26(s, 3H), 2.53(t, 2H), 2.31(s, 2H), 2.24(q, 2H), 2.12(s, 3H)

Example 2: Synthesis of (R)-3-methyl-4-(3-(methylamino)-1-phenylpropoxy)phenyl propionate

Dichloromethane (4.25 ml) and triethylamine (0.23 g, 2.31 mmol) were added to tert-butyl (R)-(3-(4-hydroxy-2-methylphenoxy)-3-phenylpropyl)(methyl)carbamate (0.85 g, 2.29 mmol), and the mixture was stirred at room temperature. Then, propanoyl chloride (0.35 g, 3.78 mmol) was added, and the mixture was stirred at room temperature for more than 1 hour. Water (2.55 ml) was added to the reaction solution to terminate the reaction, and the organic layer was extracted.

The organic layer was concentrated under reduced pressure, and dichloromethane (6.0 ml) and trifluoroacetic acid (0.78 g, 6.86 mmol) were added to the residue obtained, and the mixture was stirred at room temperature for 2 hours. Water (6.0 ml) was added to the reaction solution, and extraction was performed. The residue obtained by concentrating the extract under reduced pressure was separated by column chromatography (15% MC:MeOH) to obtain 0.60 g (yield: 80%) of a white solid compound.

1H NMR δ: 7.32-7.25(m, 5H), 7.11(d, 1H), 7.04(s, 1H), 6.91(d, 1H), 4.88(t, 1H), 3.26(s, 3H), 2.61-2.53(m, 4H), 2.24(q, 2H), 2.12(s, 3H), 1.28(t, 3H)

Example 3: Synthesis of (R)-3-methyl-4-(3-(methylamino)-1-phenylpropoxy)phenyl isobutyrate

Dichloromethane (4.25 ml) and triethylamine (0.23 g 2.31 mmol) were added to tert-butyl (R)-(3-(4-hydroxy-2-methylphenoxy)-3-phenylpropyl)(methyl)carbamate (0.85 g, 2.29 mmol), and the mixture was stirred at room temperature. Then, isobutyryl chloride (0.29 g, 2.75 mmol) was added, and the mixture was stirred at room temperature for more than 1 hour. Water (2.55 ml) was added to the reaction solution to terminate the reaction, and the organic layer was extracted.

The organic layer was concentrated under reduced pressure, and dichloromethane (6.0 ml) and trifluoroacetic acid (0.78 g, 6.86 mmol) were added to the residue obtained, and the mixture was stirred at room temperature for 2 hours. Water (6.0 ml) was added to the reaction solution, and extraction was performed. The residue obtained by concentrating the extract under reduced pressure was separated by column chromatography (15% MC:MeOH) to obtain 0.61 g (yield: 78%) of a white solid compound.

1H NMR δ: 7.32-7.25(m, 5H), 7.11(d, 1H), 7.04(s, 1H), 6.91(d, 1H), 4.88(t, 1H), 3.26(s, 3H), 2.55-2.53(m, 3H), 2.24(q, 2H), 2.12(s, 3H), 1.19(d, 6H)

Example 4: Synthesis of (R)-3-methyl-4-(3-(methylamino)-1-phenylpropoxy)phenyl cyclopropanecarboxylate

Dichloromethane (4.25 ml) and triethylamine (0.23 g 2.31 mmol) were added to tert-butyl (R)-(3-(4-hydroxy-2-methylphenoxy)-3-phenylpropyl)(methyl)carbamate (0.85 g, 2.29 mmol), and the mixture was stirred at room temperature. Then, cyclopropanecarbonyl chloride (0.29 g, 2.75 mmol) was added, and the mixture was stirred at room temperature for more than 1 hour. Water (2.55 ml) was added to the reaction solution to terminate the reaction, and the organic layer was extracted.

The organic layer was concentrated under reduced pressure, and dichloromethane (6.0 ml) and trifluoroacetic acid (0.78 g, 6.86 mmol) were added to the residue obtained, and the mixture was stirred at room temperature for 2 hours. Water (6.0 ml) was added to the reaction solution, and extraction was performed. The residue obtained by concentrating the extract under reduced pressure was separated by column chromatography (15% MC:MeOH) to obtain 0.54 g (yield: 69%) of a white solid compound.

1H NMR δ: 7.32-7.25(m, 5H), 7.11(d, 1H), 7.04(s, 1H), 6.91(d, 1H), 4.88(t, 1H), 3.26(s, 3H), 2.53(t, 3H), 2.24(q, 2H), 2.12(s, 3H), 1.61(m, 1H), 1.12-0.86(m, 4H)

Example 5: Synthesis of (R)-3-methyl-4-(3-(methylamino)-1-phenylpropoxy)phenyl dimethylcarbamate

Dichloromethane (4.25 ml) and triethylamine (0.23 g 2.31 mmol) were added to tert-butyl (R)-(3-(4-hydroxy-2-methylphenoxy)-3-phenylpropyl)(methyl)carbamate (0.85 g, 2.29 mmol), and the mixture was stirred at room temperature. Then, dimethylcarbamoyl chloride (0.30 g, 2.75 mmol) was added, and the mixture was stirred at room temperature for more than 1 hour. Water (2.55 ml) was added to the reaction solution to terminate the reaction, and the organic layer was extracted.

The organic layer was concentrated under reduced pressure, and dichloromethane (6.0 ml) and trifluoroacetic acid (0.78 g, 6.86 mmol) were added to the residue obtained, and the mixture was stirred at room temperature for 2 hours. Water (6.0 ml) was added to the reaction solution, and extraction was performed. The residue obtained by concentrating the extract under reduced pressure was separated by column chromatography (15% MC:MeOH) to obtain 0.49 g (yield: 62%) of a white solid compound.

1H NMR δ: 7.32-7.25(m, 5H), 7.11(d, 1H), 7.04(s, 1H), 6.91(d, 1H), 4.88(t, 1H), 3.27(s, 6H), 3.26(s, 3H), 2.53(t, 3H), 2.24(q, 2H), 2.12(s, 3H)

Example 6: Synthesis of 3-methyl-4-((R)-3-(methylamino)-1-phenylpropoxy)phenyl acetyl-L-alaniate

To tert-butyl (R)-(3-(4-hydroxy-2-methylphenoxy)-3-phenylpropyl)(methyl)carbamate (0.30 g, 0.81 mmol) was added dichloromethane (6.0 ml), acetyl-L-alanine (0.12 g, 0.89 mmol), and 4-dimethylaminopyridine (0.02 g, 0.20 mmol), followed by adding 1-ethyl-3-carbodiimide hydrochloride (0.23 g, 1.21 mmol), and the mixture was stirred at room temperature for 3 hours. Then, water (6.0 ml) was added to terminate the reaction, and the aqueous layer was removed.

The organic layer was concentrated under reduced pressure, and dichloromethane (6.0 ml) and trifluoroacetic acid (0.28 g, 2.42 mmol) were added to the residue obtained, and the mixture was stirred at room temperature for 2 hours. Water (6.0 ml) was added to the reaction solution, and extraction was performed. The residue obtained by concentrating the extract under reduced pressure was separated by column chromatography (15% MC:MeOH) to obtain 0.06 g (yield: 19%) of a colorless viscous substance.

1H NMR δ: 8.51(d, 1H), 7.32-7.25(m, 5H), 6.50-6.37(m, 3H), 5.11(t, 1H), 4.40-4.06(m,1H), 2.96(s,1H), 2.74(s, 3H), 2.18(s, 3H), 2.05-1.85(m, 2H), 1.83(s, 3H), 1.30-1.14(m, 5H)

Example 7: Synthesis of 3-methyl-4-((R)-3-(methylamino)-1-phenylpropoxy)phenyl acetyl-L-valinate

To tert-butyl (R)-(3-(4-hydroxy-2-methylphenoxy)-3-phenylpropyl)(methyl)carbamate (0.30 g, 0.81 mmol) was added dichloromethane (6.0 ml), acetyl-L-valine (0.14 g, 0.89 mmol), and 4-dimethylaminopyridine (0.02 g, 0.20 mmol), followed by adding 1-ethyl-3-carbodiimide hydrochloride (0.23 g, 1.21 mmol), and the mixture was stirred at room temperature for 3 hours. Then, water (6.0 ml) was added to terminate the reaction, and the aqueous layer was removed.

The organic layer was concentrated under reduced pressure, and dichloromethane (6.0 ml) and trifluoroacetic acid (0.28 g, 2.42 mmol) were added to the residue obtained, and the mixture was stirred at room temperature for 2 hours. Water (6.0 ml) was added to the reaction solution, and extraction was performed. The residue obtained by concentrating the extract under reduced pressure was separated by column chromatography (15% MC:MeOH) to obtain 0.08 g (yield: 24%) of a colorless viscous substance.

1H NMR δ: 8.32(d, 1H), 7.37-7.25(m, 5H), 6.84-6.72m, 3H), 5.53(t, 1H), 4.25(t,1H), 3.03-2.88(m,2H), 2.54(s, 3H), 2.26(s, 3H), 2.10-1.99(m, 2H), 1.89(s, 3H), 0.96(d, 6H)

Example 8: Synthesis of 3-methyl-4-((R)-3-(methylamino)-1-phenylpropoxy)phenyl acetyl-L-leucinate

Dichloromethane (6.0 ml), acetyl-L-leucine (0.15 g, 0.89 mmol), and 4-dimethylaminopyridine (0.02 g, 0.20 mmol) were added to tert-butyl (R)-(3-(4-hydroxy-2-methylphenoxy)-3-phenylpropyl)(methyl)carbamate (0.30 g, 0.81 mmol), followed by adding 1-ethyl-3-carbodiimide hydrochloride (0.23 g, 1.21 mmol). The mixture was stirred at room temperature for 3 hours. Water (6.0 ml) was added to the reaction solution to terminate the reaction, and the aqueous layer was removed.

The organic layer was concentrated under reduced pressure. Dichloromethane (6.0 ml) and trifluoroacetic acid (0.28 g, 2.42 mmol) were added to the residue obtained, and the mixture was stirred at room temperature for 2 hours. Water (6.0 ml) was added to the reaction solution, and extraction was performed. The residue obtained by concentrating the extract under reduced pressure was separated by column chromatography (15% MC:MeOH) to obtain 0.07 g (20%) of a colorless viscous substance.

1H NMR δ: 8.37 (d, 1H), 7.37-7.25(m, 5H), 6.84-6.72m, 3H), 5.53(t, 1H), 4.25(t,1H), 3.03-2.88(m,2H), 2.54(s, 3H), 2.26(s, 3H), 2.10-1.99(m, 2H), 1.86(s, 3H),1.67-1.59(m, 3H), 0.99-0.91(m, 7H)

Experimental Example 1: Pharmacokinetic Evaluation

To investigate the absorption, distribution, metabolism and excretion process of drugs in vivo, rats (Coatech Co., Ltd.) (n=3 per group) were purchased and pharmacokinetic evaluation was performed after a one-week acclimatization period. The experiment was conducted with five groups receiving oral administration (atomoxetine, 4-hydroxy atomoxetine, Examples 1, 2, 3).

The concentration of drug administration was converted and administered based on the human equivalent dose calculation method, and was set as the ratio of the same molar number based on 40 mg/day of atomoxetine. Accordingly, 4.1 mg/kg of atomoxetine, 4.4 mg/kg of 4-hydroxy atomoxetine, 5.0 mg/kg of the compound of Example 1, 5.3 mg/kg of the compound of Example 2, and 5.5 mg/kg of the compound of Example 3 were orally administered.

The food plate was replaced with water only 12 hours before drug administration, and the experiment was conducted after 12 hours of fasting. In the case of the oral administration group, a single administration was administered using an oral administration zone. Blood collection was performed before administration (0 hr) and after administration, and 300 to 400 μl of blood was collected from 10 points through the jugular vein at 0.25 hr, 0.5 hr, 1 hr, 1.5 hr, 2 hr, 4 hr, 8 hr, 12 hr, and 24 hr from the time of administration. After that, the plasma was separated by centrifugation at 3000 × g for 10 minutes, and then analyzed by LC-MS/MS. The analysis contents and pharmacokinetic results are as follows in Tables 3 and 4.

animal SD rats, 8 weeks old, weight: 180–200 g, n=3 Fasting time 12 hr group 1. Atomoxetine (4.1 mg/kg) 2. 4-hydroxy atomoxetine (4.4 mg/kg)
3. Compound of Example 1 (5.0 mg/kg)
4. Compound of Example 2 (5.3 mg/kg)
5. Compound of Example 3 (5.5 mg/kg) Route of administration Oral Blood collection time Before administration: 0 hr After administration: 0.25 hr, 0.5 hr, 1 hr, 1.5 hr, 2 hr, 4 hr, 8 hr, 12 hr and 24 hr

Parameters Atomoxetine 4-OH ATX Example 1 Example 2 Example 3 t _1/2 (hr) 4.04 ±2.43 6.95
±0.40 5.54
±0.78 13.95
±6.46 10.03
±4.31 T _max 0.33 ±0.18 0.67
±0.24 0.15 0.15 0.60
±0.64 C _max 6.82 ±3.39 3.71
±1.84 9.68
±6.45 10.63
±7.03 15.43
±13.13 AUC _0-24
(ng/ml*h) 13.86 ±1.35 6.93
±0.88 12.22
±3.33 11.11
±4.10 20.81
±12.49 AUC _0-inf 25.61 ±0.32 7.72
±0.86 13.43
±3.52 14.38
±2.89 23.13
±13.51 Vz/F 939.14 ±572.37 5755.36 ±447.49 3257.24 ±1153.09 788.71
±3715.20 5021.25 ±3569.21 CI/F 160.13 ±1.99 577.08 ±65.45 406.46
±130.09 384.59
±80.09 387.36 ±279.36

As a result of orally administering a total of five compounds of Examples 1, 2, and 3, which are prodrugs of atomoxetine, 4-hydroxy atomoxetine, and 4-hydroxy atomoxetine, the blood half-lives of the examples were significantly longer than those of atomoxetine and 4-hydroxy atomoxetine. Example 1 showed a longer half-life than atomoxetine, and examples 2 and 3 showed half-lives that were 2-fold and 1.4-fold increased, respectively, compared to 4-hydroxy atomoxetine.

For AUC0-24, the compounds of Examples 1 and 2 showed an approximately 2-fold increase compared to 4-hydroxy atomoxetine, and the compound of Example 3 showed an approximately 1.5-fold increase compared to atomoxetine and an approximately 3-fold increase compared to 4-hydroxy atomoxetine.

As such, all of the compounds of the present invention showed better pharmacokinetic results compared to atomoxetine and/or 4-hydroxy atomoxetine.

Experimental Example 2: Measurement of norepinephrine reuptake inhibition rate (IC 50 )

We aimed to determine the norepinephrine reuptake capacity in cell lines expressing the norepinephrine transporter using a kit (Neurotransmitter Transporter Uptake Assay Kit, Molecular Devices) consisting of a fluorescent substance mimicking an amine neurotransmitter and a masking dye.

HEK-293T cells stably expressing the norepinephrine transporter were seeded in a 96-well Black/Clear Bottom Plate with 6 x 104 cells in 100 μl of cell culture medium per well. After culturing for 20 h in a 37℃5% _CO2 incubator to ensure proper attachment and stabilization on the plate, the cell culture medium was removed, and 100 μl of HBSS+0.1% BSA with 20 mM HEPES solution containing the drug at the desired concentration was dispensed into each well. For the control group, 100 μl was dispensed into the same buffer solution without dissolving the drug. The cells were incubated for 30 min in a 37℃5% _CO2 incubator to allow the drug to sufficiently react with the transporter.

After that, fluorescence was measured for a total of 30 minutes in Kinetic reading mode at Ex/Em=440 nm/520 nm using a fluorescence plate reader (SpectraMax ^® ). The measured fluorescence intensity values were converted into the value of "uptake inhibition rate (%)" using the following formula, and then a dose-response curve was drawn using 4-parameter (Log) logistic regression, and the IC ₅₀ values of each drug were calculated and compared. The IC 50 values were calculated through the dose concentration-curve for the inhibition of intracellular norepinephrine reuptake through the antagonistic effect of atomoxetine, 4-hydroxy atomoxetine, and the norepinephrine transporters of Examples 1, 2, and ₃ , as shown in Table 5.

Atomoxetine 4-hydroxy atomoxetine Example 1 Example 2 Example 3 IC ₅₀ (nM) 67.46 104.9 105.4 76.01 72.98

It was confirmed that the compounds of Examples 2 and 3 showed inhibitory activity similar to that of atomoxetine in the degree of norepinephrine reuptake and superior to that of 4-hydroxy atomoxetine. This means that the compounds of the examples are easily converted to the active substance, 4-hydroxy atomoxetine, by enzymes in the body.

Claims (15)

A compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1]

In chemical formula 1, Z is any one amino acid selected from the group consisting of glycine, phenylglycine, leucine, methionine, valine, alanine, isoleucine, proline, tryptophan, tyrosine, phenylalanine, histidine, serine, cysteine, asparagine, threonine, t-leucine, glutamine, glutamic acid, aspartic acid, lysine, arginine, and 3,4-dihydroxyphenylalanine, or W; W is

and; R is H, halogen, C1-20 alkyl, _C1-20 alkoxy, _-OC1-20 alkyl, _-SC1-20 alkyl, _C1-20 alkenyl, _C1-20 alkynyl, _C3-12 cycloalkyl, heterocycloalkyl having 3 to 12 ring atoms, _C5-10 aryl, heteroaryl having 5 to 10 ring atoms, hydroxy (OH), thiol, amine, ester, carboxyl (COOH), or cyano (CN); At this time, the amino acid, alkyl, alkenyl, alkynyl and amine may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of C _1-20 alkyl, C _1-20 alkyl substituted with one or more halogens, -OC _1-20 alkyl, -SC _1-20 alkyl, ester, C _1-20 alkyl substituted with cyano, amine substituted with C _1-20 alkyl, carboxyl (COOH), halogen, cyano (CN) and C _1-20 alkylcarbonyl; The above n is an integer from 0 to 20. In the first paragraph, A compound represented by the chemical formula 1A or a pharmaceutically acceptable salt thereof: [Chemical Formula 1A]

In chemical formula 1A, The above amino acid is any one amino acid selected from the group consisting of substituted or unsubstituted glycine, phenylglycine, leucine, methionine, valine, alanine, isoleucine, proline, tryptophan, tyrosine, phenylalanine, histidine, serine, cysteine, asparagine, threonine, t-leucine, glutamine, glutamic acid, aspartic acid, lysine, arginine, and 3,4-dihydroxyphenylalanine. In the first paragraph, A compound represented by the chemical formula 1B or a pharmaceutically acceptable salt thereof: [Chemical Formula 1B]

In chemical formula 1B, wherein R is H, halogen, C _1-20 alkyl, C _1-20 alkyl substituted with one or more halogens, -OC _1-20 alkyl, -SC _1-20 alkyl, C _1-20 alkyl substituted with cyano (CN), hydroxy (OH), thiol, amine unsubstituted or substituted with C _1-20 alkyl, ester, carboxyl (COOH), cyano (CN), a substituted or unsubstituted C _3-12 cycloalkyl, a substituted or unsubstituted heterocycloalkyl having 3 to 12 ring atoms, a substituted or unsubstituted C _5-10 aryl, or a substituted or unsubstituted heteroaryl having 5 to 10 ring atoms; and wherein n is an integer of 0 to 20. In the first paragraph, A compound represented by the chemical formula 1C or a pharmaceutically acceptable salt thereof: [Chemical Formula 1C]

In chemical formula 1C, A is

,

or

And, R ₂ is hydrogen, C _1-20 alkyl, C _1-20 alkyl substituted with one or more halogens, -OC _1-20 alkyl, -SC _1-20 alkyl, ester, C _1-20 alkyl substituted with cyano, amine substituted with C _1-20 alkyl, carboxyl (COOH), halogen or cyano (CN). In the first paragraph, wherein Z is an amino acid substituted with C _1-10 alkylcarbonyl; or wherein Z is W, R is an amine substituted with C _1-10 alkyl, C _3-7 cycloalkyl, or C _1-10 alkyl, and n is 0. A compound or a pharmaceutically acceptable salt thereof. In the first paragraph, A compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is any one selected from the group below: 1) (R)-3-methyl-4-(3-(methylamino)-1-phenylpropoxy)phenyl acetate; 2) (R)-3-methyl-4-(3-(methylamino)-1-phenylpropoxy)phenyl propionate; 3) (R)-3-Methyl-4-(3-(methylamino)-1-phenylpropoxy)phenyl isobutyrate; 4) (R)-3-Methyl-4-(3-(methylamino)-1-phenylpropoxy)phenyl cyclopropanecarboxylate; 5) (R)-3-Methyl-4-(3-(methylamino)-1-phenylpropoxy)phenyl dimethylcarbamate; 6) 3-Methyl-4-((R)-3-(methylamino)-1-phenylpropoxy)phenyl acetyl-L-alaninate; 7) 3-Methyl-4-((R)-3-(methylamino)-1-phenylpropoxy)phenyl acetyl-L-valinate; and 8) 3-Methyl-4-((R)-3-(methylamino)-1-phenylpropoxy)phenyl acetyl-L-leucinate. A method for producing a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof, comprising a step of deprotecting a compound represented by the following chemical formula 2. [Chemical Formula 1]

[Chemical formula 2]

In Article 7, A method for producing a compound comprising using any one compound selected from the group consisting of:

,

,

,

,

,

,

and

. In any one of claims 1 to 6, A compound or a pharmaceutically acceptable salt thereof, wherein the compound is capable of providing 4-hydroxy atomoxetine, which is an active metabolite of atomoxetine, by an enzyme. A pharmaceutical composition for preventing or treating attention deficit hyperactivity disorder (ADHD), cognitive dysfunction or ischemic stroke, comprising a compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof. In Article 10, A pharmaceutical composition, wherein the cognitive dysfunction is any one selected from the group consisting of Alzheimer's disease, Parkinson's disease, agnosia, aphasia, apraxia, and mild cognitive impairment. In Article 10, The pharmaceutical composition above can be administered orally or topically. A method for preventing or treating attention deficit hyperactivity disorder (ADHD), cognitive dysfunction or ischemic stroke, comprising administering to a subject a compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof. Use of a compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof for the prevention or treatment of attention deficit hyperactivity disorder (ADHD), cognitive dysfunction or ischemic stroke. Use of a compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of attention deficit hyperactivity disorder (ADHD), cognitive dysfunction or ischemic stroke.

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